PS1 Alzheimer’s disease family with spastic paraplegia

Abstract

PS1 mutations are associated with classic Alzheimer's disease (AD); however, some families develop AD and spastic paraplegia (SP) with brain pathology characterized by Abeta cotton wool plaques. The authors report a variant AD family with the E280Q PS1 mutation. The fact that the same PS1 mutation can be found in patients with either variant or classic AD argues in favor of the presence of a genetic modifier. The authors have excluded that this modifier effect originates from coding sequence variations in three SP genes or from a second mutation in the other AD genes.

Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

“…The demonstration that expression of FAD-linked mutant PS1 impairs FAT of a subset of membrane proteins in peripheral nerves might also have mechanistic implications for understanding a variant clinical phenotype, termed spastic paraparesis, described in several pedigrees exhibiting early-onset AD caused by mutations in PSEN1, including a PSEN1 variant that lacks exon 9 (PS1⌬E9) (Kwok et al, 1997;Crook et al, 1998;Hiltunen et al, 2000;O'Riordan et al, 2002;Orlacchio et al, 2002;Tabira et al, 2002;Assini et al, 2003;Brooks et al, 2003;Rogaeva et al, 2003;Moretti et al, 2004;Munhoz et al, 2006). Patients with spastic paraparesis exhibit lower limb weakness and hyperreflexia associated with severe degeneration of corticospinal tracts that are among the longest motor and sensory axons in the body (Bruyn, 1992).…”

Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin–1 gene

“…In their review of 54 EOAD patients with 25 different PSEN1 mutations, Mann et al [108] [123], E280Q [141], P284L [161], L381V [113], and P436Q [69]. Tetraspasticity has been noted with Y256S [116], spasticity in N405S [184], and spastic tetraplegia at end stage in M139V [49].…”

“…CWP are large (up to 100-120 µm diameter) eosinophilic structures which may displace surrounding tissues, consisting of Aβ deposits which may be visualized by H&E staining but poorly with thioflavin S, suggesting a lack of amyloid at the core, and with poor or absent surrounding neuritic and glial responses [31, 109,161,175]. They have subsequently been observed in DelI83/M84 [156], G217D [163], V261F and P264L [165], E280G [123], E280Q [141], P284L [161], some exon 9 deletions [17] but not others [68], A431E [165], and DelT440 [75]. Appearances reminiscent of CWP were reported in L271V [89], and the "cloud-like" plaques in L250S [64] may be similar.…”

“…Neuropathological involvement of the basal ganglia and/or brainstem has been reported in insF1 (striatum) [121], G217D [163], M233V (striatum, pallidum) [70,136], V261F [48], V272A [81], and E280Q [141].…”

A novel mutation in the SPG3A gene (atlastin) in hereditary spastic paraplegia

“…Linkage analyses were performed at 6 autosomal dominant-HSP loci, SPG3A, SPG4, SPG6, SPG10, SPG12, and SPG13, using flanking microsatellite markers described previously [2]. Sequence analyses [1,3,4]. Furthermore, a specific PCR-RFLP analysis with the restriction enzyme AflIII was used to validate the identified mutation.…”